Publications by authors named "Cheng-Chang Lien"

33 Publications

Elevation of hilar mossy cell activity suppresses hippocampal excitability and avoidance behavior.

Cell Rep 2021 Sep;36(11):109702

Institute of Neuroscience, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan; Brain Research Center, National Yang Ming Chiao Tung University, Taipei 11221, Taiwan. Electronic address:

Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders.
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http://dx.doi.org/10.1016/j.celrep.2021.109702DOI Listing
September 2021

Hypothalamic Glutamate/GABA Cotransmission Modulates Hippocampal Circuits and Supports Long-Term Potentiation.

J Neurosci 2021 09 11;41(39):8181-8196. Epub 2021 Aug 11.

Taiwan International Graduate Program in Interdisciplinary Neuroscience, College of Life Sciences, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, 115, Taiwan

Subcortical input engages in cortico-hippocampal information processing. Neurons of the hypothalamic supramammillary nucleus (SuM) innervate the dentate gyrus (DG) by coreleasing two contrasting fast neurotransmitters, glutamate and GABA, and thereby support spatial navigation and contextual memory. However, the synaptic mechanisms by which SuM neurons regulate the DG activity and synaptic plasticity are not well understood. The DG comprises excitatory granule cells (GCs) as well as inhibitory interneurons (INs). Combining optogenetic, electrophysiological, and pharmacological approaches, we demonstrate that the SuM input differentially regulates the activities of different DG neurons in mice of either sex via distinct synaptic mechanisms. Although SuM activation results in synaptic excitation and inhibition in all postsynaptic cells, the ratio of these two components is variable and cell type-dependent. Specifically, dendrite-targeting INs receive predominantly synaptic excitation, whereas soma-targeting INs and GCs receive primarily synaptic inhibition. Although SuM excitation alone is insufficient to excite GCs, it enhances the GC spiking precision and reduces the latencies in response to excitatory drives. Furthermore, SuM excitation enhances the GC spiking in response to the cortical input, thereby promoting induction of long-term potentiation at cortical-GC synapses. Collectively, these findings provide physiological significance of the cotransmission of glutamate/GABA by SuM neurons in the DG network. The cortical-hippocampal pathways transfer mnemonic information during memory acquisition and retrieval, whereas subcortical input engages in modulation of communication between the cortex and hippocampus. The supramammillary nucleus (SuM) neurons of the hypothalamus innervate the dentate gyrus (DG) by coreleasing glutamate and GABA onto granule cells (GCs) and interneurons and support memories. However, how the SuM input regulates the activity of various DG cell types and thereby contributes to synaptic plasticity remains unexplored. Combining optogenetic and electrophysiological approaches, we demonstrate that the SuM input differentially regulates DG cell dynamics and consequently enhances GC excitability as well as synaptic plasticity at cortical input-GC synapses. Our findings highlight a significant role of glutamate/GABA cotransmission in regulating the input-output dynamics of DG circuits.
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http://dx.doi.org/10.1523/JNEUROSCI.0410-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482861PMC
September 2021

Neuronal basis for pain-like and anxiety-like behaviors in the central nucleus of the amygdala.

Pain 2021 Jun 25. Epub 2021 Jun 25.

Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan Institute of Neuroscience, National Yang Ming University, Taipei, Taiwan Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Abstract: Chronic pain is often accompanied by anxiety and depression disorders. Amygdala nuclei play important roles in emotional responses, fear, depression, anxiety, and pain modulation. The exact mechanism of how amygdala neurons are involved in pain and anxiety is not completely understood. The central nucleus of the amygdala contains 2 major subpopulations of GABAergic neurons that express somatostatin (SOM+) or protein kinase Cδ (PKCδ+). In this study, we found about 70% of phosphorylated ERK-positive neurons colocalized with PKCδ+ neurons in the formalin-induced pain model in mice. Optogenetic activation of PKCδ+ neurons was sufficient to induce mechanical hyperalgesia without changing anxiety-like behavior in naïve mice. Conversely, chemogenetic inhibition of PKCδ+ neurons significantly reduced the mechanical hyperalgesia in the pain model. By contrast, optogenetic inhibition of SOM+ neurons induced mechanical hyperalgesia in naïve mice and increased phosphorylated ERK-positive neurons mainly in PKCδ+ neurons. Optogenetic activation of SOM+ neurons slightly reduced the mechanical hyperalgesia in the pain model but did not change the mechanical sensitivity in naïve mice. Instead, it induced anxiety-like behavior. Our results suggest that the PKCδ+ and SOM+ neurons in the central amygdala exert different functions in regulating pain-like and anxiety-like behaviors in mice.
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http://dx.doi.org/10.1097/j.pain.0000000000002389DOI Listing
June 2021

Morpho-physiological properties and connectivity of vasoactive intestinal polypeptide-expressing interneurons in the mouse hippocampal dentate gyrus.

J Comp Neurol 2021 07 2;529(10):2658-2675. Epub 2021 Feb 2.

Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan.

The hippocampus is a key brain structure for cognitive and emotional functions. Among the hippocampal subregions, the dentate gyrus (DG) is the first station that receives multimodal sensory information from the cortex. Local-circuit inhibitory GABAergic interneurons (INs) regulate the excitation-inhibition balance in the DG principal neurons (PNs) and therefore are critical for information processing. Similar to PNs, GABAergic INs also receive distinct inhibitory inputs. Among various classes of INs, vasoactive intestinal polypeptide-expressing (VIP ) INs preferentially target other INs in several brain regions and thereby directly modulate the GABAergic system. However, the morpho-physiological characteristics and postsynaptic targets of VIP INs in the DG are poorly understood. Here, we report that VIP INs in the mouse DG are highly heterogeneous based on their morpho-physiological characteristics. In approximately two-thirds of morphologically reconstructed cells, their axons ramify in the hilus. The remaining cells project their axons exclusively to the molecular layer (15%), to both the molecular layer and hilus (10%), or throughout the entire DG layers (8%). Generally, VIP INs display variable intrinsic properties and discharge patterns without clear correlation with their morphologies. Finally, VIP INs are recruited with a long latency in response to theta-band cortical inputs and preferentially innervate GABAergic INs over glutamatergic PNs. In summary, VIP INs in the DG are composed of highly diverse subpopulations and control the DG output via disinhibition.
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http://dx.doi.org/10.1002/cne.25116DOI Listing
July 2021

Assessing the therapeutic potential of Graptopetalum paraguayense on Alzheimer's disease using patient iPSC-derived neurons.

Sci Rep 2019 12 17;9(1):19301. Epub 2019 Dec 17.

Brain Research Center, National Yang-Ming University, Taipei, 11221, Taiwan (ROC).

Alzheimer's disease (AD) is the most common type of dementia and also one of the leading causes of death worldwide. However, the underlying mechanisms remain unclear, and currently there is no drug treatment that can prevent or cure AD. Here, we have applied the advantages of using induced pluripotent stem cell (iPSC)-derived neurons (iNs) from AD patients, which are able to offer human-specific drug responsiveness, in order to evaluate therapeutic candidates for AD. Using approach involving an inducible neurogenin-2 transgene, we have established a robust and reproducible protocol for differentiating human iPSCs into glutamatergic neurons. The AD-iN cultures that result have mature phenotypic and physiological properties, together with AD-like biochemical features that include extracellular β-amyloid (Aβ) accumulation and Tau protein phosphorylation. By screening using a gene set enrichment analysis (GSEA) approach, Graptopetalum paraguayense (GP) has been identified as a potential therapeutic agent for AD from among a range of Chinese herbal medicines. We found that administration of a GP extract caused a significantly reduction in the AD-associated phenotypes of the iNs, including decreased levels of extracellular Aβ40 and Aβ42, as well as reduced Tau protein phosphorylation at positions Ser214 and Ser396. Additionally, the effect of GP was more prominent in AD-iNs compared to non-diseased controls. These findings provide valuable information that suggests moving extracts of GP toward drug development, either for treating AD or as a health supplement to prevent AD. Furthermore, our human iN-based platform promises to be a useful strategy when it is used for AD drug discovery.
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http://dx.doi.org/10.1038/s41598-019-55614-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917798PMC
December 2019

Enhanced Na -K -2Cl cotransporter 1 underlies motor dysfunction in huntington's disease.

Mov Disord 2019 06 6;34(6):845-857. Epub 2019 Mar 6.

PhD Program for Translational Medicine, China Medical University and Academia Sinica, Taipei, Taiwan.

Background: Altered γ-aminobutyric acid signaling is believed to disrupt the excitation/inhibition balance in the striatum, which may account for the motor symptoms of Huntington's disease. Na-K-2Cl cotransporter-1 is a key molecule that controls γ-aminobutyric acid-ergic signaling. However, the role of Na-K-2Cl cotransporter-1 and efficacy of γ-aminobutyric acid-ergic transmission remain unknown in Huntington's disease.

Methods: We determined the levels of Na-K-2Cl cotransporter-1 in brain tissue from Huntington's disease mice and patients by real-time quantitative polymerase chain reaction, western blot, and immunocytochemistry. Gramicidin-perforated patch-clamp recordings were used to measure the E in striatal brain slices. To inhibit Na-K-2Cl cotransporter-1 activity, R6/2 mice were treated with an intraperitoneal injection of bumetanide or adeno-associated virus-mediated delivery of Na-K-2Cl cotransporter-1 short-hairpin RNA into the striatum. Motor behavior assays were employed.

Results: Expression of Na-K-2Cl cotransporter-1 was elevated in the striatum of R6/2 and Hdh mouse models. An increase in Na-K-2Cl cotransporter-1 transcripts was also found in the caudate nucleus of Huntington's disease patients. Accordingly, a depolarizing shift of E was detected in the striatum of R6/2 mice. Expression of the mutant huntingtin in astrocytes and neuroinflammation were necessary for enhanced expression of Na-K-2Cl cotransporter-1 in HD mice. Notably, pharmacological or genetic inhibition of Na-K-2Cl cotransporter-1 rescued the motor deficits of R6/2 mice.

Conclusions: Our findings demonstrate that aberrant γ-aminobutyric acid-ergic signaling and enhanced Na-K-2Cl cotransporter-1 contribute to the pathogenesis of Huntington's disease and identify a new therapeutic target for the potential rescue of motor dysfunction in patients with Huntington's disease. © 2019 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.27651DOI Listing
June 2019

Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome.

Neurobiol Dis 2018 Jan 18;109(Pt A):25-32. Epub 2017 Sep 18.

Department of Pathology and Laboratory Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, United States; M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, One Shields Avenue, Davis, CA 95616, United States. Electronic address:

Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS. Using whole-cell patch-clamp recordings in NTS slices, we measured spontaneous inhibitory postsynaptic currents (sIPSCs), miniature IPSCs (mIPSCs), NTS-evoked IPSCs (eIPSCs), and GABA receptor (GABA-R) agonist-induced responses. Compared to those from wild-type mice, NTS neurons from Mecp2-null mice had significantly (p<0.05) reduced sIPSC amplitude, sIPSC frequency, and mIPSC amplitude but not mIPSC frequency. Mecp2-null mice also had decreased eIPSC amplitude with no change in paired-pulse ratio. The data suggest reduced synaptic receptor-mediated phasic GABA transmission in Mecp2-null mice. In contrast, muscimol (GABA-R agonist, 0.3-100μM) and THIP (selective extrasynaptic GABA-R agonist, 5μM) induced significantly greater current response in Mecp2-null mice, suggesting increased extrasynaptic receptors. Using qPCR, we found a 2.5 fold increase in the delta subunit of the GABA-Rs in the NTS in Mecp2-null mice, consistent with increased extrasynaptic receptors. As the NTS was recently found required for respiratory pathology in RTT, our results provide a mechanism for NTS dysfunction which involves shifting the balance of synaptic/extrasynaptic receptors in favor of extrasynaptic site, providing a target for boosting GABAergic inhibition in RTT.
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http://dx.doi.org/10.1016/j.nbd.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696074PMC
January 2018

K Channel Modulatory Subunits KChIP and DPP Participate in Kv4-Mediated Mechanical Pain Control.

J Neurosci 2017 04 22;37(16):4391-4404. Epub 2017 Mar 22.

Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan,

The K channel pore-forming subunit Kv4.3 is expressed in a subset of nonpeptidergic nociceptors within the dorsal root ganglion (DRG), and knockdown of Kv4.3 selectively induces mechanical hypersensitivity, a major symptom of neuropathic pain. K channel modulatory subunits KChIP1, KChIP2, and DPP10 are coexpressed in Kv4.3 DRG neurons, but whether they participate in Kv4.3-mediated pain control is unknown. Here, we show the existence of a Kv4.3/KChIP1/KChIP2/DPP10 complex (abbreviated as the Kv4 complex) in the endoplasmic reticulum and cell surface of DRG neurons. After intrathecal injection of a gene-specific antisense oligodeoxynucleotide to knock down the expression of each component in the Kv4 complex, mechanical hypersensitivity develops in the hindlimbs of rats in parallel with a reduction in all components in the lumbar DRGs. Electrophysiological data further indicate that the excitability of nonpeptidergic nociceptors is enhanced. The expression of all Kv4 complex components in DRG neurons is downregulated following spinal nerve ligation (SNL). To rescue Kv4 complex downregulation, cDNA constructs encoding Kv4.3, KChIP1, and DPP10 were transfected into the injured DRGs (defined as DRGs with injured spinal nerves) of living SNL rats. SNL-evoked mechanical hypersensitivity was attenuated, accompanied by a partial recovery of Kv4.3, KChIP1, and DPP10 surface levels in the injured DRGs. By showing an interdependent regulation among components in the Kv4 complex, this study demonstrates that K channel modulatory subunits KChIP1, KChIP2, and DPP10 participate in Kv4.3-mediated mechanical pain control. Thus, these modulatory subunits could be potential drug targets for neuropathic pain. Neuropathic pain, a type of moderate to severe chronic pain resulting from nerve injury or disorder, affects 6.9%-10% of the global population. However, less than half of patients report satisfactory pain relief from current treatments. K channels, which act to reduce nociceptor activity, have been suggested to be novel drug targets for neuropathic pain. This study is the first to show that K channel modulatory subunits KChIP1, KChIP2, and DPP10 are potential drug targets for neuropathic pain because they form a channel complex with the K channel pore-forming subunit Kv4.3 in a subset of nociceptors to selectively inhibit mechanical hypersensitivity, a major symptom of neuropathic pain.
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http://dx.doi.org/10.1523/JNEUROSCI.1619-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596563PMC
April 2017

K Channel Kv3.4 Is Essential for Axon Growth by Limiting the Influx of Ca into Growth Cones.

J Neurosci 2017 04 20;37(17):4433-4449. Epub 2017 Mar 20.

Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan

Membrane excitability in the axonal growth cones of embryonic neurons influences axon growth. Voltage-gated K (Kv) channels are key factors in controlling membrane excitability, but whether they regulate axon growth remains unclear. Here, we report that Kv3.4 is expressed in the axonal growth cones of embryonic spinal commissural neurons, motoneurons, dorsal root ganglion neurons, retinal ganglion cells, and callosal projection neurons during axon growth. Our (cultured dorsal spinal neurons of chick embryos) and (developing chick spinal commissural axons and rat callosal axons) findings demonstrate that knockdown of Kv3.4 by a specific shRNA impedes axon initiation, elongation, pathfinding, and fasciculation. In cultured dorsal spinal neurons, blockade of Kv3.4 by blood depressing substance II suppresses axon growth via an increase in the amplitude and frequency of Ca influx through T-type and L-type Ca channels. Electrophysiological results show that Kv3.4, the major Kv channel in the axonal growth cones of embryonic dorsal spinal neurons, is activated at more hyperpolarized potentials and inactivated more slowly than it is in postnatal and adult neurons. The opening of Kv3.4 channels effectively reduces growth cone membrane excitability, thereby limiting excessive Ca influx at subthreshold potentials or during Ca-dependent action potentials. Furthermore, excessive Ca influx induced by an optogenetic approach also inhibits axon growth. Our findings suggest that Kv3.4 reduces growth cone membrane excitability and maintains [Ca] at an optimal concentration for normal axon growth. Accumulating evidence supports the idea that impairments in axon growth contribute to many clinical disorders, such as autism spectrum disorders, corpus callosum agenesis, Joubert syndrome, Kallmann syndrome, and horizontal gaze palsy with progressive scoliosis. Membrane excitability in the growth cone, which is mainly controlled by voltage-gated Ca (Cav) and K (Kv) channels, modulates axon growth. The role of Cav channels during axon growth is well understood, but it is unclear whether Kv channels control axon outgrowth by regulating Ca influx. This report shows that Kv3.4, which is transiently expressed in the axonal growth cones of many types of embryonic neurons, acts to reduce excessive Ca influx through Cav channels and thus permits normal axon outgrowth.
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http://dx.doi.org/10.1523/JNEUROSCI.1076-16.2017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596659PMC
April 2017

Causal Evidence for the Role of Specific GABAergic Interneuron Types in Entorhinal Recruitment of Dentate Granule Cells.

Sci Rep 2016 11 10;6:36885. Epub 2016 Nov 10.

Institute of Neuroscience, National Yang-Ming University, 155, Section 2, Li-Nong Street, Taipei 112, Taiwan.

The dentate gyrus (DG) is the primary gate of the hippocampus and controls information flow from the cortex to the hippocampus proper. To maintain normal function, granule cells (GCs), the principal neurons in the DG, receive fine-tuned inhibition from local-circuit GABAergic inhibitory interneurons (INs). Abnormalities of GABAergic circuits in the DG are associated with several brain disorders, including epilepsy, autism, schizophrenia, and Alzheimer disease. Therefore, understanding the network mechanisms of inhibitory control of GCs is of functional and pathophysiological importance. GABAergic inhibitory INs are heterogeneous, but it is unclear how individual subtypes contribute to GC activity. Using cell-type-specific optogenetic perturbation, we investigated whether and how two major IN populations defined by parvalbumin (PV) and somatostatin (SST) expression, regulate GC input transformations. We showed that PV-expressing (PV+) INs, and not SST-expressing (SST+) INs, primarily suppress GC responses to single cortical stimulation. In addition, these two IN classes differentially regulate GC responses to θ and γ frequency inputs from the cortex. Notably, PV+ INs specifically control the onset of the spike series, whereas SST+ INs preferentially regulate the later spikes in the series. Together, PV+ and SST+ GABAergic INs engage differentially in GC input-output transformations in response to various activity patterns.
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http://dx.doi.org/10.1038/srep36885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5103275PMC
November 2016

Gain of BDNF Function in Engrafted Neural Stem Cells Promotes the Therapeutic Potential for Alzheimer's Disease.

Sci Rep 2016 06 6;6:27358. Epub 2016 Jun 6.

Institute of Basic Medical Science, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Stem cell-based therapy is a potential treatment for neurodegenerative diseases, but its application to Alzheimer's disease (AD) remains limited. Brain-derived neurotrophic factor (BDNF) is critical in the pathogenesis and treatment of AD. Here, we present a novel therapeutic approach for AD treatment using BDNF-overexpressing neural stem cells (BDNF-NSCs). In vitro, BDNF overexpression was neuroprotective to beta-amyloid-treated NSCs. In vivo, engrafted BDNF-NSCs-derived neurons not only displayed the Ca(2+)-response fluctuations, exhibited electrophysiological properties of mature neurons and integrated into local brain circuits, but recovered the cognitive deficits. Furthermore, BDNF overexpression improved the engrafted cells' viability, neuronal fate, neurite complexity, maturation of electrical property and the synaptic density. In contrast, knockdown of the BDNF in BDNF-NSCs diminished stem cell-based therapeutic efficacy. Together, our findings indicate BDNF overexpression improves the therapeutic potential of engrafted NSCs for AD via neurogenic effects and neuronal replacement, and further support the feasibility of NSC-based ex vivo gene therapy for AD.
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http://dx.doi.org/10.1038/srep27358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893631PMC
June 2016

Wiring Specificity and Synaptic Diversity in the Mouse Lateral Central Amygdala.

J Neurosci 2016 Apr;36(16):4549-63

Institute of Neuroscience, Institute of Brain Science, Brain Research Center, and

Unlabelled: The central amygdala (CeA) nucleus, a subcortical structure composed of mostly GABA-releasing (GABAergic) neurons, controls fear expression via projections to downstream targets in the hypothalamus and brainstem. The CeA consists of the lateral (CeL) and medial (CeM) subdivisions. The CeL strongly gates information transfer to the CeM, the main output station of the amygdala, but little is known about the functional organization of local circuits in this region. Using cluster analysis, we identified two major electrophysiologically distinct CeL neuron classes in mouse amygdala slices, the early-spiking (ES) and late-spiking (LS) neurons. These two classes displayed distinct autaptic transmission. Compared with LS neurons, ES neurons had strong and depressing autapses, which enhanced spike-timing precision. With multiple patch-clamp recordings, we found that CeL neurons made chemical, but not electrical, synapses. Analysis of individual connections revealed cannabinoid type 1 receptor-mediated suppression of the ES, but not of the LS cell output synapse. More interestingly, the efficacy of the ES→LS or LS→ES synapse was ~2-fold greater than that of the LS→LS or ES→ES synapse. When tested at 20 Hz, synapses between different neurons, but not within the same class, were markedly depressing and were more powerful to sculpt activity of postsynaptic neurons. Moreover, neurons of different classes also form synapses with higher degree of connectivity. We demonstrate that ES and LS neurons represent two functionally distinct cell classes in the CeL and interactions between presynaptic and postsynaptic neurons dictate synaptic properties between neurons.

Significance Statement: The central lateral amygdala (CeL) is a key node in fear circuits, but the functional organization of local circuits in this region is largely unknown. The CeL consists of mostly GABAergic inhibitory neurons with different functional and molecular features. Here, we report that the presynaptic cell class determines functional properties of autapses and cannabinoid-mediated modulation of synaptic transmission between neurons, whereas presynaptic versus postsynaptic cell classes dictate the connectivity, efficacy, and dynamics of GABAergic synapses between any two neurons. The wiring specificity and synaptic diversity have a great impact on neuronal output in amygdala inhibitory networks. Such synaptic organizing principles advance our understanding of the significance of physiologically defined neuronal phenotypes in amygdala inhibitory networks.
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http://dx.doi.org/10.1523/JNEUROSCI.3309-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6601824PMC
April 2016

Type VI adenylyl cyclase negatively regulates GluN2B-mediated LTD and spatial reversal learning.

Sci Rep 2016 Mar 2;6:22529. Epub 2016 Mar 2.

Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan.

The calcium-sensitive type VI adenylyl cyclase (AC6) is a membrane-bound adenylyl cyclase (AC) that converts ATP to cAMP under stimulation. It is a calcium-inhibited AC and integrates negative inputs from Ca(2+) and multiple other signals to regulate the intracellular cAMP level. In the present study, we demonstrate that AC6 functions upstream of CREB and negatively controls neuronal plasticity in the hippocampus. Genetic removal of AC6 leads to cyclase-independent and N-terminus of AC6 (AC6N)-dependent elevation of CREB expression, and enhances the expression of GluN2B-containing NMDA receptors in hippocampal neurons. Consequently, GluN2B-dependent calcium signaling and excitatory postsynaptic current, long-term depression, and spatial reversal learning are enhanced in the hippocampus of AC6(-/-) mice without altering the gross anatomy of the brain. Together, our results suggest that AC6 negatively regulates neuronal plasticity by modulating the levels of CREB and GluN2B in the hippocampus.
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http://dx.doi.org/10.1038/srep22529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4773765PMC
March 2016

Differential Recruitment of Dentate Gyrus Interneuron Types by Commissural Versus Perforant Pathways.

Cereb Cortex 2016 06 4;26(6):2715-27. Epub 2015 Jun 4.

Institute of Neuroscience Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Gamma-aminobutyric acidergic (GABAergic) interneurons (INs) in the dentate gyrus (DG) provide inhibitory control to granule cell (GC) activity and thus gate incoming signals to the hippocampus. However, how various IN subtypes inhibit GCs in response to different excitatory input pathways remains mostly unknown. By using electrophysiology and optogenetics, we investigated neurotransmission of the hilar commissural pathway (COM) and the medial perforant path (MPP) to the DG in acutely prepared mouse slices. We found that the short-term dynamics of excitatory COM-GC and MPP-GC synapses was similar, but that the dynamics of COM- and MPP-mediated inhibition measured in GCs was remarkably different, during theta-frequency stimulation. This resulted in the increased inhibition-excitation (I/E) ratios in single GCs for COM stimulation, but decreased I/E ratios for MPP stimulation. Further analysis of pathway-specific responses in identified INs revealed that basket cell-like INs, total molecular layer- and molecular layer-like cells, received greater excitation and were more reliably recruited by the COM than by the MPP inputs. In contrast, hilar perforant path-associated and hilar commissural-associational pathway-related-like cells were minimally activated by both inputs. These results demonstrate that distinct IN subtypes are preferentially recruited by different inputs to the DG, and reveal their relative contributions in COM-mediated feedforward inhibition.
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http://dx.doi.org/10.1093/cercor/bhv127DOI Listing
June 2016

ASIC-dependent LTP at multiple glutamatergic synapses in amygdala network is required for fear memory.

Sci Rep 2015 May 19;5:10143. Epub 2015 May 19.

1] Institute of Neuroscience, National Yang-Ming University, Taipei 112, Taiwan [2] Institute of Brain Science, National Yang-Ming University, Taipei 112, Taiwan [3] Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.

Genetic variants in the human ortholog of acid-sensing ion channel-1a subunit (ASIC1a) gene are associated with panic disorder and amygdala dysfunction. Both fear learning and activity-induced long-term potentiation (LTP) of cortico-basolateral amygdala (BLA) synapses are impaired in ASIC1a-null mice, suggesting a critical role of ASICs in fear memory formation. In this study, we found that ASICs were differentially expressed within the amygdala neuronal population, and the extent of LTP at various glutamatergic synapses correlated with the level of ASIC expression in postsynaptic neurons. Importantly, selective deletion of ASIC1a in GABAergic cells, including amygdala output neurons, eliminated LTP in these cells and reduced fear learning to the same extent as that found when ASIC1a was selectively abolished in BLA glutamatergic neurons. Thus, fear learning requires ASIC-dependent LTP at multiple amygdala synapses, including both cortico-BLA input synapses and intra-amygdala synapses on output neurons.
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http://dx.doi.org/10.1038/srep10143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437300PMC
May 2015

Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety.

Eur J Neurosci 2015 Jun 4;41(12):1553-68. Epub 2015 May 4.

Graduate institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.

Although ASIC4 is a member of the acid-sensing ion channel (ASIC) family, we have limited knowledge of its expression and physiological function in vivo. To trace the expression of this ion channel, we generated the ASIC4-knockout/CreERT(2)-knockin (Asic4(Cre) (ERT) (2)) mouse line. After tamoxifen induction in the Asic4(Cre) (ERT)(2)::CAG-STOP(floxed)-Td-tomato double transgenic mice, we mapped the expression of ASIC4 at the cellular level in the central nervous system (CNS). ASIC4 was expressed in many brain regions, including the olfactory bulb, cerebral cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, brain stem, cerebellum, spinal cord and pituitary gland. Colocalisation studies further revealed that ASIC4 was expressed mainly in three types of cells in the CNS: (i) calretinin (CR)-positive and/or vasoactive intestine peptide (VIP)-positive interneurons; (ii) neural/glial antigen 2 (NG2)-positive glia, also known as oligodendrocyte precursor cells; and (iii) cerebellar granule cells. To probe the possible role of ASIC4, we hypothesised that ASIC4 could modulate the membrane expression of ASIC1a and thus ASIC1a signaling in vivo. We conducted behavioral phenotyping of Asic4(Cre) (ERT)(2) mice by screening many of the known behavioral phenotypes found in Asic1a knockouts and found ASIC4 not involved in shock-evoked fear learning and memory, seizure termination or psychostimulant-induced locomotion/rewarding effects. In contrast, ASIC4 might play an important role in modulating the innate fear response to predator odor and anxious state because ASIC4-mutant mice showed increased freezing response to 2,4,5-trimethylthiazoline and elevated anxiety-like behavior in both the open-field and elevated-plus maze. ASIC4 may modulate fear and anxiety by counteracting ASIC1a activity in the brain.
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http://dx.doi.org/10.1111/ejn.12905DOI Listing
June 2015

G206D Mutation of Presenilin-1 Reduces Pen2 Interaction, Increases Aβ42/Aβ40 Ratio and Elevates ER Ca(2+) Accumulation.

Mol Neurobiol 2015 Dec 15;52(3):1835-1849. Epub 2014 Nov 15.

Institute of Brain Science, National Yang-Ming University, Taipei, Taiwan.

Early-onset familial Alzheimer's disease (AD) is most commonly associated with the mutations in presenilin-1 (PS1). PS1 is the catalytic component of the γ-secretase complex, which cleaves amyloid precursor protein to produce amyloid-β (Aβ), the major cause of AD. Presenilin enhancer 2 (Pen2) is critical for activating γ-secretase and exporting PS1 from endoplasmic reticulum (ER). Among all the familial AD-linked PS1 mutations, mutations at the G206 amino acid are the most adjacent position to the Pen2 binding site. Here, we characterized the effect of a familial AD-linked PS1 G206D mutation on the PS1-Pen2 interaction and the accompanied alteration in γ-secretase-dependent and -independent functions. We found that the G206D mutation reduced PS1-Pen2 interaction, but did not abolish γ-secretase formation and PS1 endoproteolysis. For γ-secretase-dependent function, the G206D mutation increased Aβ42 production but not Notch cleavage. For γ-secretase-independent function, this mutation disrupted the ER calcium homeostasis but not lysosomal calcium homeostasis and autophagosome maturation. Impaired ER calcium homeostasis may due to the reduced mutant PS1 level in the ER. Although this mutation did not alter the cell survival under stress, both increased Aβ42 ratio and disturbed ER calcium regulation could be the mechanisms underlying the pathogenesis of the familial AD-linked PS1 G206D mutation.
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http://dx.doi.org/10.1007/s12035-014-8969-1DOI Listing
December 2015

Rapid dynamic changes of dendritic inhibition in the dentate gyrus by presynaptic activity patterns.

J Neurosci 2014 Jan;34(4):1344-57

Institute of Neuroscience, National Yang-Ming University, Taipei 112, Taiwan, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan, and Department of Anesthesiology, Mackay Memorial Hospital, Mackay Junior College of Medicine, Nursing and Management College; and Department of Medicine, Mackay Medical College, Taipei, Taiwan.

The dentate gyrus (DG) serves as a primary gate to control information transfer from the cortex to the hippocampus. Activation of incoming cortical inputs results in rapid synaptic excitation followed by slow GABA-mediated (GABAergic) synaptic inhibition onto DG granule cells (GCs). GABAergic inhibitory interneurons (INs) in the DG comprise fast-spiking (FS) and non-fast-spiking (non-FS) cells. Anatomical analyses of DG INs reveal that FS cells are soma-targeting INs, whereas non-FS cells are dendrite-targeting INs. These two IN classes are differentially recruited by excitatory inputs and in turn provide exquisite spatiotemporal control over GC activity. Yet, little is known how FS and non-FS cells transform their presynaptic dynamics into varying postsynaptic response amplitudes. Using paired recordings in rat hippocampal slices, we show that inhibition in the DG is dominated by somatic GABAergic inputs during periods of sparse presynaptic activity, whereas dendritic GABAergic inputs are rapidly shifted to powerful and sustained inhibition during periods of intense presynaptic activity. The variant dynamics of dendritic inhibition is dependent on presynaptic IN subtypes and their activity patterns and is attributed to Ca(2+)-dependent increases in the probability of release and the size of the readily releasable pool. Furthermore, the degree of dynamic GABA release can be reduced by blocking voltage-gated K(+) channels, which increases the efficacy of dendrite-targeting IN output synapses during sparse firing. Such rapid dynamic modulation of dendritic inhibition may act as a frequency-dependent filter to prevent overexcitation of GC dendrites and thus set the excitatory-inhibitory synaptic balance in the DG circuits.
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http://dx.doi.org/10.1523/JNEUROSCI.2566-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705299PMC
January 2014

Mirror-image pain is mediated by nerve growth factor produced from tumor necrosis factor alpha-activated satellite glia after peripheral nerve injury.

Pain 2014 May 18;155(5):906-920. Epub 2014 Jan 18.

Institute of Neuroscience, National Yang-Ming University, Taipei 112, Taiwan Department of Anesthesiology, Mackay Memorial Hospital, Mackay Junior College of Medicine, Nursing and Management, and Department of Medicine, Mackay Medical College, Taipei, Taiwan Department of Neurosurgery, Taipei City Hospital Zhongxing Branch, Taipei 103, Taiwan.

Mirror-image pain is characterized by mechanical hypersensitivity on the uninjured mirror-image side. Recent reports favor central mechanisms, but whether peripheral mechanisms are involved remains unclear. We used unilateral spinal nerve ligation (SNL) to induce mirror-image pain in rats. On the mirror-image (contralateral) side, we found that satellite glia in the dorsal root ganglion (DRG) were activated, whereas macrophages/Schwann cells in the DRG and astrocytes/oligodendrocytes/microglia in the dorsal spinal cord were not. Subsequently, an increase in nerve growth factor (NGF) was detected in the contralateral DRG, and NGF immunoreactivity was concentrated in activated satellite glia. These phenomena were abolished if fluorocitrate (a glial inhibitor) was intrathecally injected before SNL. Electrophysiological recordings in cultured small DRG neurons showed that exogenous NGF enhanced nociceptor excitability. Intrathecal injection of NGF into naive rats induced long-lasting mechanical hypersensitivity, similar to SNL-evoked mirror-image pain. Anti-NGF effectively relieved SNL-evoked mirror-image pain. In the contralateral DRG, the SNL-evoked tumor necrosis factor alpha (TNF-α) increase, which started later than in the ipsilateral DRG and cerebrospinal fluid, occurred earlier than satellite glial activation and the NGF increase. Intrathecal injection of TNF-α into naive rats not only activated satellite glia to produce extra NGF in the DRG but also evoked mechanical hypersensitivity, which could be attenuated by anti-NGF injection. These results suggest that after SNL, satellite glia in the contralateral DRG are activated by TNF-α that diffuses from the injured side via cerebrospinal fluid, which then activates satellite glia to produce extra NGF to enhance nociceptor excitability, which induces mirror-image pain.
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http://dx.doi.org/10.1016/j.pain.2014.01.010DOI Listing
May 2014

Ba2+- and bupivacaine-sensitive background K+ conductances mediate rapid EPSP attenuation in oligodendrocyte precursor cells.

J Physiol 2013 Oct 12;591(19):4843-58. Epub 2013 Aug 12.

C.-C. Lien: Institute of Neuroscience, National Yang-Ming University, 155, Section 2, Li-Nong Street, Taipei 11221, Taiwan.

Glutamatergic transmission onto oligodendrocyte precursor cells (OPCs) may regulate OPC proliferation, migration and differentiation. Dendritic integration of excitatory postsynaptic potentials (EPSPs) is critical for neuronal functions, and mechanisms regulating dendritic propagation and summation of EPSPs are well understood. However, little is known about EPSP attenuation and integration in OPCs. We developed realistic OPC models for synaptic integration, based on passive membrane responses of OPCs obtained by simultaneous dual whole-cell patch-pipette recordings. Compared with neurons, OPCs have a very low value of membrane resistivity, which is largely mediated by Ba(2+)- and bupivacaine-sensitive background K(+) conductances. The very low membrane resistivity not only leads to rapid EPSP attenuation along OPC processes but also sharpens EPSPs and narrows the temporal window for EPSP summation. Thus, background K(+) conductances regulate synaptic responses and integration in OPCs, thereby affecting activity-dependent neuronal control of OPC development and function.
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http://dx.doi.org/10.1113/jphysiol.2013.257113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3800458PMC
October 2013

Cell type-specific dependency on the PI3K/Akt signaling pathway for the endogenous Epo and VEGF induction by baicalein in neurons versus astrocytes.

PLoS One 2013 19;8(7):e69019. Epub 2013 Jul 19.

Division of Neurology, Department of Pediatrics, the Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia, United States of America.

The neuroprotective effect of baicalein is generally attributed to inhibition of 12/15-lipoxygenase (12/15-LOX) and suppression of oxidative stress, but recent studies showed that baicalein also activates hypoxia-inducible factor-α (HIF1α) through inhibition of prolyl hydrolase 2 (PHD2) and activation of the phosphatidylinositide-3 kinase (PI3K)/Akt signaling pathway. Yet, the significance and regulation of prosurvival cytokines erythropoietin (Epo) and vascular endothelial growth factor (VEGF), two transcriptional targets of HIF1α, in baicalein-mediated neuroprotection in neurons and astrocytes remains unknown. Here we investigated the causal relationship between the PI3K/Akt signaling pathway and Epo/VEGF expression in baicalein-mediated neuroprotection in primary rat cortical neurons and astrocytes. Our results show that baicalein induced Epo and VEGF expression in a HIF1α- and PI3K/Akt-dependent manner in neurons. Baicalein also protected neurons against excitotoxicity in a PI3K- and Epo/VEGF-dependent manner without affecting neuronal excitability. In contrast, at least a 10-fold higher concentration of baicalein was needed to induce Epo/VEGF production and PI3K/Akt activity in astrocytes for protection of neurons. Moreover, only baicalein-induced astrocytic VEGF, but not Epo expression requires HIF1α, while PI3K/Akt signaling had little role in baicalein-induced astrocytic Epo/VEGF expression. These results suggest distinct mechanisms of baicalein-mediated Epo/VEGF production in neurons and astrocytes for neuroprotection, and provide new insights into the mechanisms and potential of baicalein in treating brain injury in vivo.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0069019PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3719842PMC
February 2014

Acid-sensing ion channel-1a is not required for normal hippocampal LTP and spatial memory.

J Neurosci 2013 Jan;33(5):1828-32

Institute of Neuroscience, Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.

Acid-sensing ion channel-1a (ASIC1a) is localized in brain regions with high synaptic density and is thought to contribute to synaptic plasticity, learning, and memory. A prominent hypothesis is that activation of postsynaptic ASICs promotes depolarization, thereby augmenting N-methyl-d-aspartate receptor function and contributing to the induction of long-term potentiation (LTP). However, evidence for activation of postsynaptic ASICs during neurotransmission has not been established. Here, we re-examined the role of ASIC1a in LTP in the hippocampus using pharmacological and genetic approaches. Our results showed that a tarantula peptide psalmotoxin, which profoundly blocked ASIC currents in the hippocampal neurons, had no effect on LTP. Similarly, normal LTP was robustly generated in ASIC1a-null mice. A further behavioral analysis showed that mice lacking ASIC1a had normal performance in hippocampus-dependent spatial memory. In summary, our results indicate that ASIC1a is not required for hippocampal LTP and spatial memory. We therefore propose that the role of ASIC1a in LTP and spatial learning should be reassessed.
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http://dx.doi.org/10.1523/JNEUROSCI.4132-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6619135PMC
January 2013

Mutations in KCND3 cause spinocerebellar ataxia type 22.

Ann Neurol 2012 Dec;72(6):859-69

Department of Neurology, National Yang-Ming University School of Medicine, Taipei, Taiwan; Brain Research Center, National Yang-Ming University, Taipei, Taiwan.

Objective: To identify the causative gene in spinocerebellar ataxia (SCA) 22, an autosomal dominant cerebellar ataxia mapped to chromosome 1p21-q23.

Methods: We previously characterized a large Chinese family with progressive ataxia designated SCA22, which overlaps with the locus of SCA19. The disease locus in a French family and an Ashkenazi Jewish American family was also mapped to this region. Members from all 3 families were enrolled. Whole exome sequencing was performed to identify candidate mutations, which were narrowed by linkage analysis and confirmed by Sanger sequencing and cosegregation analyses. Mutational analyses were also performed in 105 Chinese and 55 Japanese families with cerebellar ataxia. Mutant gene products were examined in a heterologous expression system to address the changes in protein localization and electrophysiological functions.

Results: We identified heterozygous mutations in the voltage-gated potassium channel Kv4.3-encoding gene KCND3: an in-frame 3-nucleotide deletion c.679_681delTTC p.F227del in both the Chinese and French pedigrees, and a missense mutation c.1034G>T p.G345V in the Ashkenazi Jewish family. Direct sequencing of KCND3 further identified 3 mutations, c.1034G>T p.G345V, c.1013T>C p.V338E, and c.1130C>T p.T377M, in 3 Japanese kindreds. Immunofluorescence analyses revealed that the mutant p.F227del Kv4.3 subunits were retained in the cytoplasm, consistent with the lack of A-type K(+) channel conductance in whole cell patch-clamp recordings.

Interpretation: Our data identify the cause of SCA19/22 in patients of diverse ethnic origins as mutations in KCND3. These findings further emphasize the important role of ion channels as key regulators of neuronal excitability in the pathogenesis of cerebellar degeneration.
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http://dx.doi.org/10.1002/ana.23701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085146PMC
December 2012

TDP-43 regulates the mammalian spinogenesis through translational repression of Rac1.

Acta Neuropathol 2012 Aug 4;124(2):231-45. Epub 2012 Jul 4.

Institute of Molecular Biology, Academia Sinica, Nankang, Taipei, 115, Taiwan.

Impairment of learning and memory is a significant pathological feature of many neurodegenerative diseases including FTLD-TDP. Appropriate regulation and fine tuning of spinogenesis of the dendrites, which is an integral part of the learning/memory program of the mammalian brain, are essential for the normal function of the hippocampal neurons. TDP-43 is a nucleic acid-binding protein implicated in multi-cellular functions and in the pathogenesis of a range of neurodegenerative diseases including FTLD-TDP and ALS. We have combined the use of single-cell dye injection, shRNA knockdown, plasmid rescue, immunofluorescence staining, Western blot analysis and patch clamp electrophysiological measurement of primary mouse hippocampal neurons in culture to study the functional role of TDP-43 in mammalian spinogenesis. We found that depletion of TDP-43 leads to an increase in the number of protrusions/spines as well as the percentage of matured spines among the protrusions. Significantly, the knockdown of TDP-43 also increases the level of Rac1 and its activated form GTP-Rac1, a known positive regulator of spinogenesis. Clustering of the AMPA receptors on the dendritic surface and neuronal firing are also induced by depletion of TDP-43. Furthermore, use of an inhibitor of Rac1 activation negatively regulated spinogenesis of control hippocampal neurons as well as TDP-43-depleted hippocampal neurons. Mechanistically, RT-PCR assay and cycloheximide chase experiments have indicated that increases in Rac1 protein upon TDP-43 depletion is regulated at the translational level. These data together establish that TDP-43 is an upstream regulator of spinogenesis in part through its action on the Rac1 → GTP-Rac1 → AMPAR pathway. This study provides the first evidence connecting TDP-43 with the GTP-Rac1 → AMPAR regulatory pathway of spinogenesis. It establishes that mis-metabolism of TDP-43, as occurs in neurodegenerative diseases with TDP-43 proteinopathies, e.g., FTLD-TDP, would alter its homeostatic cellular concentration, thus leading to impairment of hippocampal plasticity.
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http://dx.doi.org/10.1007/s00401-012-1006-4DOI Listing
August 2012

GABA is depolarizing in hippocampal dentate granule cells of the adolescent and adult rats.

J Neurosci 2012 Jan;32(1):62-7

Institute of Neuroscience and Brain Research Center, School of Life Sciences, National Yang-Ming University, Taipei 112, Taiwan.

GABAergic signaling in hippocampal pyramidal neurons undergoes a switch from depolarizing to hyperpolarizing during early neuronal development. Whether such a transformation of GABAergic action occurs in dentate granule cells (DGCs), located at the first stage of the hippocampal trisynaptic circuit, is unclear. Here, we use noninvasive extracellular recording to monitor the effect of synaptically released GABA on the DGC population. We find that GABAergic responses in adolescent and adult rat DGCs are still depolarizing from rest. Using a morphologically realistic DGC model, we show that GABAergic action, depending on its precise timing and location, can have either an excitatory or inhibitory role in signal processing in the dentate gyrus.
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http://dx.doi.org/10.1523/JNEUROSCI.3393-11.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6621339PMC
January 2012

High-density expression of Ca2+-permeable ASIC1a channels in NG2 glia of rat hippocampus.

PLoS One 2010 Sep 10;5(9). Epub 2010 Sep 10.

Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Department of Anesthesiology, Cheng Hsin General Hospital, Taipei, Taiwan.

NG2 cells, a fourth type of glial cell in the mammalian CNS, undergo reactive changes in response to a wide variety of brain insults. Recent studies have demonstrated that neuronally expressed acid-sensing ion channels (ASICs) are implicated in various neurological disorders including brain ischemia and seizures. Acidosis is a common feature of acute neurological conditions. It is postulated that a drop in pH may be the link between the pathological process and activation of NG2 cells. Such postulate immediately prompts the following questions: Do NG2 cells express ASICs? If so, what are their functional properties and subunit composition? Here, using a combination of electrophysiology, Ca2+ imaging and immunocytochemistry, we present evidence to demonstrate that NG2 cells of the rat hippocampus express high density of Ca2+-permeable ASIC1a channels compared with several types of hippocampal neurons. First, nucleated patch recordings from NG2 cells revealed high density of proton-activated currents. The magnitude of proton-activated current was pH dependent, with a pH for half-maximal activation of 6.3. Second, the current-voltage relationship showed a reversal close to the equilibrium potential for Na+. Third, psalmotoxin 1, a blocker specific for the ASIC1a channel, largely inhibited proton-activated currents. Fourth, Ca2+ imaging showed that activation of proton-activated channels led to an increase of [Ca2+]i. Finally, immunocytochemistry showed co-localization of ASIC1a and NG2 proteins in the hippocampus. Thus the acid chemosensor, the ASIC1a channel, may serve for inducing membrane depolarization and Ca2+ influx, thereby playing a crucial role in the NG2 cell response to injury following ischemia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0012665PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2937019PMC
September 2010

Functional identification of an outwardly rectifying pH- and anesthetic-sensitive leak K(+) conductance in hippocampal astrocytes.

Eur J Neurosci 2010 Sep 28;32(5):725-35. Epub 2010 Jul 28.

Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Section 2, Li-Nong St., Taipei, Taiwan.

Astrocytes function as spatial K(+) buffers by expressing a rich repertoire of K(+) channels. Earlier studies suggest that acid-sensitive tandem-pore K(+) channels, mainly TWIK-related acid-sensitive K(+) (TASK) channels, mediate part of the passive astroglial membrane conductance. Here, using a combination of electrophysiology and pharmacology, we investigated the presence of TASK-like conductance in hippocampal astrocytes of rat brain slices. Extracellular pH shifts to below 7.4 (or above 7.4) induced a prominent inward (or outward) current in astrocytes in the presence of tetrodotoxin, a Na(+) channel blocker, and 4,4'-diisothiocyanatostilbene-2,2'-disulfonate, a co-transporter blocker. The pH-sensitive current was insensitive to quinine, a potent blocker of tandem-pore K(+) channels including TWIK-1 and TREK-1 channels. Voltage-clamp analysis revealed that the pH-sensitive current exhibited weak outward rectification with a reversal potential of -112 mV, close to the Nernst equilibrium potential for K(+) . Furthermore, the current-voltage relationship was well fitted with the Goldman-Hodgkin-Katz current equation for the classical open-rectifier 'leak' K(+) channel. The pH-sensitive K(+) current was potentiated by TASK channel modulators such as the volatile anesthetic isoflurane but depressed by the local anesthetic bupivacaine. However, unlike TASK channels, the pH-sensitive current was insensitive to Ba(2+) and quinine. Thus, the molecular identity of the pH-sensitive leak K(+) channel is unlikely to be attributable to TASK channels. Taken together, our results suggest a novel yet unknown leak K(+) channel underlying the pH- and anesthetic-sensitive background conductance in hippocampal astrocytes.
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http://dx.doi.org/10.1111/j.1460-9568.2010.07323.xDOI Listing
September 2010

Cell type-specific expression of acid-sensing ion channels in hippocampal interneurons.

J Neurosci 2010 May;30(19):6548-58

Institute of Neuroscience and Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.

Acid-sensing ion channels (ASICs), a member of the degenerin/epithelial Na+ channel superfamily, are widely expressed in the mammalian CNS. Accumulating evidence suggests that ASIC current density is higher in GABAergic interneurons than that in glutamatergic pyramidal neurons (PNs) in the hippocampus. Such differential expression of ASICs in cortical networks is thought to be a key element for seizure termination. However, GABAergic interneurons are highly diverse; it is unclear whether the functional expression of ASICs differs in distinct GABAergic interneuron subtypes. Moreover, the subunit composition of ASICs in individual GABAergic interneurons remains unknown. By combining patch-clamp recording and single-cell reverse transcription (RT)-PCR analysis, we correlated ASIC currents with their gene expression in acute rat hippocampal slices. The results yielded several surprising findings. First, ASIC current density of oriens lacunosum-moleculare (O-LM) cells in the CA1 region, a classical type of dendrite-targeting interneuron, is 6 times greater than that of fast-spiking basket cells (BCs) in the dentate gyrus, a major class of soma-targeting interneuron. Second, the recovery of ASICs from desensitization is slowest in BCs, intermediate in PNs, and fastest in O-LM cells. Third, the tarantula venom psalmotoxin 1, the specific blocker for ASIC1a homomers, inhibits ASIC currents in BCs but not in O-LM cells. Finally, single-cell RT-PCR analysis reveals coexpression of ASIC1a and ASIC2 subunit transcripts in O-LM cells, whereas only ASIC1a subunit transcript is detected in most BCs. Thus, differential expression of ASICs in inhibitory microcircuits likely contributes to the distinct roles of GABAergic interneurons in normal physiology and pathophysiology.
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http://dx.doi.org/10.1523/JNEUROSCI.0582-10.2010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6632567PMC
May 2010

Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus.

J Physiol 2006 Jul 11;574(Pt 1):229-43. Epub 2006 May 11.

Physiologisches Institut, Universität Freiburg, Hermann-Herder-Str. 7, D-79104 Freiburg, Germany.

Hyperpolarization-activated channels (Ih or HCN channels) are widely expressed in principal neurons in the central nervous system. However, Ih in inhibitory GABAergic interneurons is less well characterized. We examined the functional properties of Ih in fast-spiking basket cells (BCs) of the dentate gyrus, using hippocampal slices from 17- to 21-day-old rats. Bath application of the Ih channel blocker ZD 7288 at a concentration of 30 microm induced a hyperpolarization of 5.7 +/- 1.5 mV, an increase in input resistance and a correlated increase in apparent membrane time constant. ZD 7288 blocked a hyperpolarization-activated current in a concentration-dependent manner (IC50, 1.4 microm). The effects of ZD 7288 were mimicked by external Cs+. The reversal potential of Ih was -27.4 mV, corresponding to a Na+ to K+ permeability ratio (PNa/PK) of 0.36. The midpoint potential of the activation curve of Ih was -83.9 mV, and the activation time constant at -120 mV was 190 ms. Single-cell expression analysis using reverse transcription followed by quantitative polymerase chain reaction revealed that BCs coexpress HCN1 and HCN2 subunit mRNA, suggesting the formation of heteromeric HCN1/2 channels. ZD 7288 increased the current threshold for evoking antidromic action potentials by extracellular stimulation, consistent with the expression of Ih in BC axons. Finally, ZD 7288 decreased the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal granule cells, the main target cells of BCs, to 70 +/- 4% of the control value. In contrast, the amplitude of mIPSCs was unchanged, consistent with the presence of Ih in inhibitory terminals. In conclusion, our results suggest that Ih channels are expressed in the somatodendritic region, axon and presynaptic elements of fast-spiking BCs in the hippocampus.
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http://dx.doi.org/10.1113/jphysiol.2005.104042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1817792PMC
July 2006

Visual stimuli-induced LTD of GABAergic synapses mediated by presynaptic NMDA receptors.

Nat Neurosci 2006 Mar 12;9(3):372-80. Epub 2006 Feb 12.

Division of Neurobiology, Department of Molecular and Cell Biology, Helen Wills Neuroscience Institute, University of California Berkeley, California 94720-3200, USA.

Local GABA (gamma-aminobutyric acid) circuits contribute to sensory experience-dependent refinement of neuronal connections in the developing nervous system, but whether GABAergic synapses themselves can be rapidly modified by sensory stimuli is largely unknown. Here we report that repetitive light stimuli or theta burst stimulation (TBS) of the optic nerve in the developing Xenopus retinotectal system induces long-term potentiation (LTP) of glutamatergic inputs but long-term depression (LTD) of GABAergic inputs to the same tectal neuron. The LTD is due to a reduction in presynaptic GABA release and requires activation of presynaptic NMDA (N-methyl-D-aspartate) receptors (NMDARs) and coincident high-level GABAergic activity. Thus, the presynaptic NMDAR may function as a coincidence detector for adjacent glutamatergic and GABAergic activities, leading to coordinated synaptic modification by sensory experience.
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http://dx.doi.org/10.1038/nn1649DOI Listing
March 2006
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